Virtually all women will use progesterone as a therapy at some point in their lives; despite this, very little research has been conducted on alternative phytoprogestins available in consumable botanical supplements. The breadth of circumstances that employ progestin-containing therapies is striking: endometriosis, fibroids, menopausal symptoms, contraception, and cancers, in all affect hundreds of millions of women worldwide. Botanical dietary supplements are consumed by millions of women. Our preliminary data suggest that the supplements women are consuming contain phytoprogestins that interact with progesterone receptors and modulate hormonal signaling, which if consumed by women could have an impact on various pathologies such as endometriosis, fibroids, fertility modulation, and prevention and treatment of endometrial cancers. Alternatively, women consuming estrogens should use them in combination with progestins to oppose estrogenic action in the uterus that increases the risk of hyperplasia and cancer. From a diverse panel of plants selected based on a series of in house screening results, studies for women's health benefits in the UIC Botanical Center, and a literature report that screened over 150 traditionally used plants for the presence of phytoprogestins, we will synergize with the mission of the UIC Center and test our hypothesis that progesterone-like compounds are present in botanicals and exert tissue-specific gene induction in the breast and uterus. We will 1) Identify the component(s) responsible for the progesterone-like activity in botanicals and develop a high-throughput screen that allows us to detect and identify them from complex mixtures of natural products, 2) Biologically characterize progestins from botanical extracts in regard to their safety and efficacy by measuring their activation of tissue-specific markers and their specificity for androgen receptors and glucocorticoid receptors, and 3) Elucidate the interaction between phytoprogestins and phytoestrogens on tissue specific gene regulation of the breast and uterus. Since progestins are used for hormone replacement, birth control, emergency contraception, and the treatment of endometriosis, fibroids, and uterine cancer, identifying if and when women are consuming these molecules is critical for their safe and effective use. Women are already exposing themselves to many of these progesterone-like molecules in botanical dietary supplements, and we have no knowledge of where these compounds are present, of their tissue specific effects, or of what their overall impact is on women's health. In order for a woman to safely and effectively use or avoid these compounds, they need to be identified and quantified. This study will provide an important avenue for the identification and characterization of selective natural progesterone compounds from botanical extracts. Therefore, a more focused approach at identifying progestins and characterizing their action - especially from commonly used botanical supplements - is of imminently high impact.